Multiple Sclerosis
Multiple Sclerosis (MS) is a common neurological disease affecting more than 1 million people worldwide (EMEA CHMP Guideline on MS, 2007). Its prevalence rate varies between races and geographical latitude, ranging from more than 100 per 100,000 in Northern and Central Europe to 50 per 100,000 in Southern Europe. MS is an inflammatory condition that damages the myelin of the Central Nervous System (CNS; the brain, spinal cord and optic nerves) and causes neurologic impairment and, frequently, severe disability. It is the commonest cause of neurological disability in young and middle-aged adults and has a major physical, psychological, social and financial impact on patients and bodies responsible for health care.
The etiology of MS remains unknown. It is generally assumed that MS is mediated by some kind of autoimmune process, an abnormal response of the body's immune system against the myelin in the CNS, possibly triggered by infection and superimposed upon a genetic predisposition. Research to date has identified the immune cells which attack the myelin, some of the factors causing them to attack, and some of the sites or receptors on the attacking cells that appear to be attracted to the myelin to begin the destructive process. However, the specific target on the myelin is yet to be identified. MS is characterized by chronic patchy inflammation of the CNS with demyelinization and gliosis (scarring). It is thought that progression of lesions in MS might have two components: an active immunological aspect and a degenerative aspect; it is unknown to what extent these are causally interrelated.
Two principal clinical courses were classified 20 years ago by the US National Multiple Sclerosis Society; relapse remitting MS and chronic progressive MS. These were further refined in 1996 by Lublin & Reingold into four clinical courses of the disease, currently recognized as: Relapsing Remitting MS (RRMS), Secondary Progressive MS (SPMS), Primary Progressive MS (PPMS) and Progressive Relapsing MS (PRMS). Each of these categories can be mild, moderate, or severe. Other very rare forms of MS also exist. More specifically, RRMS is the initial course in 80 to 85% of people diagnosed with MS and is characterized by unpredictable clearly defined relapses (flare-ups or exacerbations) of worsened neurological functioning with partial or complete recovery periods (remissions), during which no disease progression occurs. Remissions last for a period of months or years and impairments suffered during attacks may resolve or leave sequelae. Following an initial period of RRMS, many sufferers develop a secondary-progressive disease course in which the disease worsens more steadily between acute attacks, without definite periods of remission, or stable periods. Occasional relapses and minor remissions may occur. Approximately 50% of RRMS patients develop SPMS within 10 years, and after 25 to 30 years, the percentage rises to 90%. Approximately 10-15% of people diagnosed with MS have PPMS, which is characterized by slowly worsening neurologic function from the outset, with no distinct relapses or remissions.
The rate of progression may vary over time, with occasional periods of stability and temporary minor improvements. The age of onset is later than for other clinical courses. In PRMS (approximately, 5% of people diagnosed with MS), patients experience steady neurological decline from disease onset, but with clear attacks of worsening function. They may or may not experience some recovery following these relapses, but the disease continues to progress without remissions. Finally, the term clinically isolated syndrome (CIS) applies to those patients who have suffered a single clinical event but do not comply with the diagnostic criteria for definite MS.
While the four main courses of MS are currently defined according to clinical characteristics, there is increasing evidence of distinct pathological and pathogenic mechanisms between the different courses. Relapses are considered the clinical expression of acute inflammatory focal lesions whereas progression is considered to reflect the occurrence of demyelination, axonal loss and gliosis. These differences are important as they reflect differences in prognosis and because disease modifying drugs are currently effective only in the relapsing types of MS, i.e. patients either with a RRMS form or a SPMS form that are suffering relapses. Patients with relapsing MS constitute a common target for therapeutic treatments, indeed, RRMS and SPMS can be considered as different stages of the same disease while PPMS may imply different processes.
There is currently no treatment proven to slow the progression of PPMS, nor curative treatment for MS. In general, current therapeutic approaches include: symptomatic treatment, corticosteroids for acute relapses, and treatment aimed to modify the course of the disease (disease modifying drugs).
Symptomatic treatments refer to all therapies applied to improve symptoms caused by the disease: fatigue, spasticity, ataxia, weakness, bladder and bowel disturbances, sexual dysfunction, pain, tremor, paroxysmal manifestations, visual impairment, psychological problems, cognitive dysfunction and other associated conditions that can improve with non specific treatments. Disease modifying drugs are therapies aimed to decrease the relapse rate or modify relapses and to diminish the accumulation of disability in time (Table 1). While disease modifying medications may impact how quickly patients move from RRMS to SPMS and potentially the overall number of patients developing this course, long term data are not yet available. Currently approved therapies to modify the MS course target the immunological processes of the disease. Most of them are considered to act as immunomodulators but their mechanisms of action have not been completely elucidated. Immunosupressants or cytotoxic agents are also used in some patients after failure of conventional therapies. Based on the immunological nature of the disease, combination therapy targeting different parts of the immune processes may also be a possible strategy.
TABLE 1FDA Approved Disease Modifying Therapies for MSFDAap-Active agentDrugprovalApproved IndicationinterferonBetaseron1993Treatment of relapsing forms ofbeta 1bMS and SPMS with relapses; andafter a first clinical episode withMRI features consistent with MSinterferonExtavia2009Treatment of relapsing forms ofbeta 1bMS and SPMS with relapses; andafter a first clinical episode withMRI features consistent with MSinterferonAvonex1996Treatment of relapsing forms ofbeta 1aMS, and for a first clinical episodeif MRI features consistent with MSare also presentglatiramerCopaxone1996Treatment RRMS; and for a firstacetateclinical episode if MRI featuresconsistent with MSmitoxantroneNovantrone2000Treatment of RRMS andprogressive-relapsing or SPMSinterferonRebif2002Treatment of relapsing MSbeta 1anatalizumabTysabri2004/Treatment of relapsing forms of2006*MS as a monotherapy (not usedin combination with any otherdisease-modifying medication).*Voluntarily withdrawn from the market on Feb. 28, 2005; US FDA March 2006 Advisory Panel recommended for re-approval.
Despite these approved therapies, the unmet medical need in the MS field remains substantial, even for relapsing MS patients treated early and in particular for the populations of PPMS and relapse-free SPMS (rfSPMS). Several reasons can be given for this:                None of the available drugs completely stop the disease process.        MS progression can be at an advanced stage before any diagnosis is made and advanced MS is not highly responsive to treatment with any of the available drugs.        None of the drugs have been shown to be effective in rfSPMS or PPMS, subpopulations in which inflammation appears to be less prominent.        There is a suspicion that inflammation alone cannot entirely explain the progressive neurodegeneration, particularly later in the disease.        Many of the standard treatments require regular injections or infusions which, considering the chronic nature of this disease, impact negatively on the patient's adherence to treatment, quality of life and can lead to a common side effect of injection site reactions.        MS follows a highly heterogeneous disease progression, yet patient-optimized treatment, e.g. weight-adjusted dosing, is not developed in the currently available drugs.        Long-term treatment regimens using corticosteroids are associated with numerous detrimental side effects, with its benefits possibly outweighed by potential complications.Role of c-Kit and Mast Cells in Inflammation        
Mast cells (MC) are predominantly found in tissues at the interface between the host and the external environment, such as lung, connective tissue, lymphoid tissue, gut mucosa, and skin. They develop from a common circulating CD34+/c-Kit+/CD13+/FcεRI− hematopoietic progenitor representing a single lineage, which gives rise to different phenotypes after migrating into peripheral tissues. Immature MC progenitors circulate in the bloodstream and differentiate in tissues. These differentiation and proliferation processes are influenced by cytokines, notably Stem Cell Factor (SCF), also termed Kit ligand (KL), Steel factor (SL) or Mast Cell Growth Factor (MCGF). The SCF receptor is encoded by the proto-oncogene c-Kit. It has been shown that SCF regulates the migration, maturation, proliferation, and activation of MCs in vivo—injection of recombinant SCF into rodents, primates, or humans, results in an increase in MC numbers at both the site of injection and at distant sites.
Binding of SCF to the c-Kit receptor induces c-Kit dimerization followed by its transphosphorylation, leading to the recruitment and activation of various intracytoplasmic substrates. These activated substrates induce multiple intracellular signaling pathways responsible for cell proliferation and activation. MCs are characterized by their heterogeneity, not only regarding tissue location and structure but also at functional and histochemical levels. MC activation is followed by the controlled release of a variety of mediators that are essential for the defense of the organism against invading pathogens. By contrast, in the case of hyperactivation of MCs, uncontrolled hypersecretion of these mediators is deleterious for the body. MCs produce a large variety of mediators categorized here into three groups:                Preformed granule-associated mediators (histamines, proteoglycans, and neutral proteases);        Lipid-derived mediators (prostaglandins, thromboxanes and leucotrienes);        Various cytokines (including the interleukins: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8 and tumor necrosis factor alpha TNF-α, GM-CSF, MIP-1α, MIP-1β and IFN-γ).        
Human MCs constitutively express a number of receptors for different biological molecules. Among these receptors, whose ligation induces the activation of MCs, the best known is the high affinity receptor for IgE (FcER1). Binding of IgE-multivalent antigen complexes to FcER1 leads to receptor aggregation and internalization, signaling, and degranulation. This can be accompanied by the transcription of cytokine genes, thus, perpetuating the inflammatory response. Moreover, triggering of MCs leads to the secretion of diverse pre-formed and/or de novo synthesized mediators, such as vasoactive amines (histamine, serotonin), sulfated proteoglycans, lipid mediators (prostaglandin D2, leucotrienes), growth factors, proteases, cytokines and chemokines as described previously. These mediators can, alone or in synergy with macrophage-derived and T cell-derived cytokines, generate a complex inflammatory response and induce the recruitment and activation of inflammatory cells to the site of degranulation.